JPH11507338A - Method for synthesizing benzo [b] thiophene - Google Patents

Abstract

  (57) [Summary] The present invention relates to a novel method for synthesizing 2-arylbenzo [b] thiophenes and novel intermediates therefor.

Description

DETAILED DESCRIPTION OF THE INVENTION                       Synthetic method of benzo [b] thiophene   The invention relates to benzo [b] thiophenes, in particular 2-aryl-benzo [b] thiophenes To a novel synthesis method.   Benzo [b] thiophene has been produced by many different synthetic routes. Most One method that is also widely used is the oxidative cyclization of o-mercaptocinnamic acid. This route is limited to the production of benzo [b] thiophen-2-carboxylate. 2-f Phenylbenzo [b] thiophene is 2-phenylthioacetaldehyde dialkyl Produced by acid-catalyzed cyclization of cetal. Unsubstituted benzo [b] thiophene is styrene Produced by catalytic condensation of ren and sulfur. 3-Substituted benzo [b] thiophenes Produced by acid-catalyzed cyclization of reel thiomethyl ketone, this route Limited to the production of quinbenzo [b] thiophene (Campaigne, "Thiophenes and the ir Benzo Derivatives: (iii) Synthesis and Applications ", in Comprehensi ve Heterocyclic Chemistry (Katritzky and Rees, eds.), Volume IV, Part III , 863-934 (1984)). 3-Chloro-2-phenylbenzo [b] thiophene is It is produced by the reaction of nylacetylene with sulfur dichloride (Barton and Zika, J. et al. Org. Chem. , 35, 1729-1733 (1970)). Benzo [b] thiophene is styrylsul It has also been produced by the thermal decomposition of foxide. However, the yield is low and extremely This high temperature makes this route unsuitable for production-scale synthesis (Ando, J. Chem.). . Soc., Chem. Comm. , 704-705 (1975)).   The method for producing 6-hydroxy-2- (4-hydroxyphenyl) benzo [b] thiophene And U.S. Pat. Nos. 4,133,814 and 4,380,635. These patents One method described is α- (3-methoxyphenylthio) -4-methoxyacetophenone Acid catalyzed intramolecular cyclization / rearrangement of Raw polyphosphoric acid at about 85 ° C to about 90 ° C The reaction of the starting compounds in yields two regioisomeric products: Methoxy-2- (4-methoxyphenyl) -benzo [b] thiophene and 4-methoxy-2- (4-meth G An about 3: 1 mixture of (xyphenyl) benzo [b] thiophene is obtained. These isomers ben Zo [b] thiophene is co-precipitated from the reaction mixture to give a mixture containing both compounds. To obtain a single regioisomer, such as by chromatography or fractional crystallization, It is necessary to separate regioisomers. Therefore, from readily available starting materials There is a current need for an efficient and regiospecific synthesis of 2-arylbenzo [b] thiophenes Is being used.   The present invention relates to a method for synthesizing benzo [b] thiophene. Specifically, the present invention provides a compound of the formula: [Where R₁Is hydrogen, C₁-C_FourAlkoxy, arylalkoxy, halo, amino Yes, R_TwoIs hydrogen, C₁-C_FourAlkoxy, arylalkoxy, halo, amino] A method for producing a compound represented by the formula: [Where R₁And R_TwoIs as defined above.] And treating the compound with an acid catalyst. The present invention uses the formula The present invention also relates to the compound of VI and its production method.   The term "acid catalyst" refers to a Lewis or Bronsted acid. Representative Lewis The acids are zinc chloride, zinc iodide, aluminum chloride and aluminum bromide . Typical Bronsted acids include inorganic acids such as sulfuric and phosphoric acids, acetic acid and the like. And carboxylic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfo Acid, 1-naphthalenesulfonic acid, 1-butanesulfonic acid, ethanesulfonic acid, 4-E Tylbenzenesulfonic acid, 1-hexanesulfonic acid, 1,5-naphthalenedisulfonic acid , 1-octanesulfonic acid, camphorsulfonic acid, trifluoromethanesulfone Acids and sulfonic acids, such as p-toluenesulfonic acid, and Nafion® Polymer ally, such as Amberlyst® or Amberlite® Sulfonic acid. Preferred acids used to catalyze the process of the present invention are It is sulfonic acid or polymer sulfonic acid. More preferably, the acid catalyst is Sulfonic acid, benzenesulfonic acid, camphorsulfonic acid and p-toluenes It is a sulfonic acid such as sulfonic acid. The most preferred acid catalyst is p-toluene sulfo Acid.   In the above formula, the term `` C<sub>1</sub>-C<sub>Four</sub>Alkoxy '' refers to methoxy, ethoxy, n-propoxy , Isopropoxy, n-butoxy, t-butoxy and similar groups. The term "halo" represents a fluoro, chloro, bromo or iodo group.   The term "C<sub>1</sub>-C<sub>6</sub>"Alkyl" represents a linear or branched alkyl chain having 1 to 6 carbon atoms. You. Typical C<sub>1</sub>-C<sub>6</sub>Alkyl groups include methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopench And n-hexyl and 2-methylpentyl. The term "C<sub>1</sub>-C<sub>Four</sub>Alkyl "Represents a straight-chain or branched-chain alkyl having 1 to 4 carbon atoms, and methyl, ethyl, n-pro Including pill, isopropyl, n-butyl, sec-butyl, i-butyl and t-butyl.   The term "aryl" refers to groups such as phenyl and substituted phenyl. the term" `` Substituted phenyl '' refers to halo, hydroxy, nitro, C₁-C_FourAlkyl, C₁-C_FourAlkoki One or more selected from the group consisting of trichloromethyl and trifluoromethyl Represents a phenyl group substituted by a further moiety. Examples of substituted phenyl groups include 4- Chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichloro Phenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibu Lomophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4-hydro Xyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl Phenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethyl Ruphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl , 2,6-difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphen Nil, 2,4,6-trifluorophenyl, 2-trifluoro-methylphenyl, 2-chloro B-5-trifluoromethylphenyl, 3,5-bis- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 4-hydro Xy-3-methylphenyl, 3,5-dimethyl, 4-hydroxyphenyl, 2-methyl-4-ni Trophenyl and 4-methoxy-2-nitrophenyl and the like are included.   The term "arylalkyl" refers to a C having one or more aryl groups.₁-C_Four Represents alkyl. Representative of this group are benzyl, o-nitrobenzyl, p- Nitrobenzyl, p-halobenzyl (p-chlorobenzyl, p-bromobenzyl, p-yo 1-phenylethyl, 2-phenylethyl, 3-phenylp) Propyl, 4-phenylbutyl, 2-methyl-2-phenylpropyl, (2,6-dichlorophenyl Enyl) methyl, bis (2,6-dichlorophenyl) methyl, (4-hydroxyphenyl ) Methyl, (2,4-dinitrophenyl) methyl, diphenylmethyl, triphenylmethyl Tyl, (p-methoxyphenyl) diphenylmethyl, bis (p-methoxyphenyl) meth Butyl and bis (2-nitrophenyl) methyl.   The term "arylalkoxy" refers to a C having one or more aryl groups.₁-C_Four Represents an alkoxy group. Representatives of this group include benzyloxy, o-nitro Benzyloxy, p-nitrobenzyloxy, p-halobenzyloxy (p-chloro Benzyloxy, p-bromobenzyloxy, p-iodobenzyloxy), 1-phenyl Luethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy , 2-methyl-2-phenylpropoxy, (2,6-dichlorophenyl) methoxy, bis (2 , 6-Dichlorophenyl) methoxy, (4-hydroxyphenyl) methoxy, (2,4-dini (Trophenyl) methoxy, diphenylmethoxy, triphenylmethoxy, (p-meth Ki (Ciphenyl) diphenylmethoxy, bis (p-methoxyphenyl) methoxy and (2-nitrophenyl) methoxy and the like.   The term `` heat-labile or acid-labile C_Two-C_TenAlkyl, C_Four-C_TenAlkenyl or ant (C₁-C_TenAlkyl) group "is a sulfoxide (under heat or by an acid-catalyzed treatment) Represents a group that is easily removed from the (SO) group. Heat-labile or acid-labile C_Two-C_TenAlkyl The group is a straight or branched chain having 2 to 10 carbon atoms having at least one β-hydrogen atom. It is a branched alkyl chain. Typical heat-labile or acid-labile C_Two-C_TenAlkyl group , Ethyl, n-propyl, i-propyl, 1,1-dimethylpropoyl, n-butyl, sec- Butyl, t-butyl, 1,1-dimethylbutyl, 2-methylbutyl, 3-methylbutyl, 1- Methylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,4-dimethylbutyl , 3,3-dimethylbutyl, n-pentyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, n-hexyl and the like are included. Heat-resistant or Acid instability C_Four-C_TenAn alkenyl group is unsaturated at least at one site and has a β-hydrogen Straight or branched having 4 to 10 carbon atoms having either an atom or a δ-hydrogen atom Is an alkenyl chain. Typical heat-labile or acid-labile C_Four-C_TenAlkenyl group Is 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2- Methyl-3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2- Pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl-3-pe Unenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-methyl-4-pent Thenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 2-hexenyl, 3- Hexenyl, 4-hexenyl and 5-hexenyl and the like. The term heat easiness or Is an acid labile aryl (C₁-C_TenAlkyl) further comprises one or more aryl Heat-labile or acid-labile C containing a group and an aryl-substituted methyl group_Two-C_TenAlkyl group Represents Representative aryl (C₁-C_TenAlkyl) groups include benzyl and diphenylmethyl , Triphenylmethyl, p-methoxybenzyl, 2-phenylethyl, 2-phenylp Ropyl and 3-phenylpropyl and the like.   The starting compound of the compound and the method of the present invention can be prepared by a number of routes. Can be. One method for preparing compounds of Formula II is shown in Scheme 1.                                 Reaction formula 1   Generally, a compound of formula VII is prepared by reacting a compound of formula VII in the presence of a Lewis acid._ThreeMercaptan To convert to styryl sulfide.   More particularly, a compound of formula VII wherein R₁And R_TwoIs as defined above) Treat with a Lewis acid such as titanium (IV) chloride. The reaction is carried out in dry tetrahydrofura. The reaction is carried out at a temperature of about 0 ° C. to about 35 ° C. in an anhydrous organic solvent such as a solvent. About 15 minutes to about 1 After time, the reaction mixture is treated with the formula HSR_Three(Where R_ThreeIs heat-labile or acid-labile C₁-C_TenA Lucil, C_Four-C_TenAlkenyl or aryl (C₁-C_TenAlkyl) group) Treat with butane and amino base. Preferably, the mercaptan and amine salt The group is added as a solution in the reaction solvent. A typical amine base is triethylamine. You. After addition of the mercaptan and amine base, the reaction is typically brought to about 35 ° C. Heat to a temperature of from about 65 ° C, preferably about 50 ° C. The product of this reaction can be crystallized or Purification by techniques well known in the chemical arts, such as chromatography Can be.   Next, a compound of formula VIII (where R₁And R_TwoIs as defined above, and R_ThreeIs easy Thermal or acid labile C_Two-C_TenAlkyl, C_Four-C_TenAlkenyl or aryl (C₁-C_{1 0} Oxidation) to give compounds of formula II. Suitable for this reaction Oxidizing agents such as peracetic acid and m-chloroperoxybenzoic acid and hydrogen peroxide Is a peracid. This oxidation reaction typically involves toluene, methylene chloride, chloro It is carried out in an organic solvent such as form or carbon tetrachloride. Using peracid as oxidizing agent When performed, the reaction is generally carried out at a temperature of about -30 ° C to about 15 ° C, preferably about -20 ° C. It is. The product of this reaction is easily purified by crystallization. R_ThreeIs t-butyl When this occurs, the crystalline product of this reaction series is the E regioisomer of Formula II.   R_ThreeHas a tertiary carbon near the sulfur atom, Z isomerism of the compound of formula II The body can be prepared selectively by the second route shown in Scheme II.                                 Reaction formula 2   Generally, a compound of formula IX that is benzyl alcohol is_ThreeSH Mercapta To give a compound of formula X which is a benzyl sulfide. This benzyls The sulfide is reacted with a strong base to form the benzyl anion, which is Condensed with hide. The condensation product is reacted with an acid chloride and the resulting intermediate is Treatment with strong bases gives styryl sulfide, a compound of formula VIIIZ . Next, the styryl sulfide is oxidized with an oxidizing agent to obtain a compound of formula IIZ.   The first step in the synthesis of Z styryl sulfoxide compounds is Conversion to a compound of formula X which is benzyl chloride. Compounds of Formula IX where R_Two Is as defined above) and formula R_ThreeSH (where R_ThreeIs a tertiary carbon near the sulfur atom Heat-labile or acid-labile C with atoms_Two-C_TenAlkyl, C_Four-C_TenAlkenyl or Is aryl (C₁-C_TenAlkyl)) in the presence of a Lewis acid The reaction yields a compound of formula X that is a benzyl sulfide. This ingredient Suitable Lewis acids for substitution include zinc bromide, zinc chloride, zinc iodide, iron (III) chloride, Titanium (IV) chloride, aluminum trichloride and aluminum tribromide, preferably Zinc iodide. Generally, the reaction is carried out with 1,2-dichloroethane or methyl chloride. It is performed in an organic solvent such as ren. If the reaction is performed at room temperature, the reaction is It will be completed soon.   The benzyl sulfide is reacted with a strong base to form a benzyl anion. this Strong bases suitable for the reaction include sodium methoxide, sodium ethoxide, and lithium. Gold such as um ethoxide, lithium t-butoxide and potassium t-butoxide Alkoxides, sodium hydride, and n-butyllithium, t-butyllithium And lithium alkyls such as sec-butyllithium and methyllithium. I will. The preferred strong base for this reaction is n-butyl lithium. This reaction A preferred solvent for is dry tetrahydrofuran. n-butyl lithium When used as a strong base, the reaction is carried out at a temperature from about -35 ° C to about -15 ° C.   Condensates benzyl anion with benzaldehyde to form an intermediate condensation product . The benzaldehyde has the general formula p-R₁(C₆H_Four) CHO (where R₁Is hydrogen, C₁-C_FourA Alkoxy, arylalkoxy, halo or amino). Preferably Produces benzyl anion and adds benzaldehyde to a cold solution of benzyl anion. To form a condensation product in the reaction system.   Treating the condensation product with an acid chloride produces an intermediate compound. Typical acid chloride Is an acyl chloride such as acetyl chloride and benzoyl chloride, methanesulfonyl Chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride, ethane Sulfonyl chloride, isopropylsulfonyl chloride and p-toluenesulfo Sulfonyl chlorides such as nyl chloride, methoxycarbonyl chloride and Alkoxycarbonyl chlorides such as benzyloxycarbonyl chloride, and And dialkylaminocarbocarbons such as N, N-dimethylaminocarbonyl chloride Nyl chloride, preferably sulfonyl chloride, is included. Preferably, the condensation product Immediately after the formation of the product, methanesulfonyl chloride is added to the reaction mixture.   The intermediate compound is reacted with a second strong base to form styryl sulfide, a compound of formula VIIIZ Compound (where R₁, R_TwoAnd R_ThreeIs as defined above). This reaction Suitable strong bases include sodium methoxide, sodium ethoxide, lithium Metal oxides such as ethoxide, lithium t-butoxide and potassium t-butoxide Lucoxide, sodium hydride, n-butyllithium, t-butyllithium, sec-butyllithium Alkyl lithiums such as tyl lithium and methyl lithium, and sodium Muamide, magnesium diisopropylamide and lithium diisopropylamide Metal amides such as amides are included. A preferred strong base for this reaction is potassium Um t-butoxide. Generally, the reaction is conducted at about 15 ° C. to about room temperature, preferably at room temperature. Done at warm.   Oxidation of styryl sulfide produces the corresponding styryl sulfoxide. This Oxidizing agents suitable for the reaction of acetic acid include peracetic acid and m-chloroperoxybenzoic acid. Acids, organic peroxides such as t-butyl peroxide, and hydrogen peroxide. Like Alternatively, the oxidizing agent is peracetic acid. Typically, this oxidation involves toluene, benzene , Xylene, methanol, ethanol, methyl acetate, ethyl acetate, methylene chloride Organic solvents such as 1,2-dichloroethane or chloroform, preferably chloride Performed in methylene. This oxidation can be performed at a temperature from about -40 ° C to about 0 ° C. .   Alternatively, R_ThreeHas a tertiary carbon near the sulfur atom, Using a sulfide intermediate (compound of formula X), the compound of formula II, which is a styryl sulfoxide, A mixture of the E and Z isomers of the product can be prepared. This synthesis is shown in Scheme 3. You.                                 Reaction formula 3   The benzyl sulfide prepared as described above is oxidized to give the corresponding benzyl sulfide. Produces oxide. This benzylsulfoxide is reacted with a strong base, Neon is condensed with benzaldehyde. Reacting the condensation product with the acid chloride to obtain Reacting the intermediate compound with a second strong base to form styryl sulfoxide. Generate.   A compound of formula X that is benzyl sulfide, where R_TwoIs as defined above, R_ThreeIs a heat-labile or acid-labile C having a tertiary carbon atom near the sulfur atom._Two-C_Ten Alkyl, C_Four-C_TenAlkenyl or aryl (C₁-C_TenOxidation) And yields the corresponding benzylsulfoxide, a compound of Formula XI. This reaction Suitable oxidizing agents are peracids such as peracetic acid and m-chloroperoxybenzoic acid, Organic peroxides such as t-butyl oxide, and hydrogen peroxide. Preferably The oxidizing agent is peracetic acid. Typically, this oxidation involves toluene, benzene, Len, methanol, ethanol, methyl acetate, ethyl acetate, methylene chloride, 1,2 -In an organic solvent such as dichloroethane or chloroform, preferably at about -30 ° C It is carried out at a temperature of about 5 ° C.   A compound of formula XI that is benzylsulfoxide, where R_TwoAnd R_ThreeAgree with the above Is reacted with a strong base to produce the benzyl anion. Suitable for this reaction Strong bases include sodium methoxide, sodium ethoxide, lithium ethoxide. Metal alcohols such as sid, lithium t-butoxide and potassium t-butoxide Oxide, sodium hydride, n-butyllithium, t-butyllithium, sec-butyl Alkyllithiums such as lithium and methyllithium, and sodium Amide, magnesium diisopropylamide and lithium diisopropylamide And metal amides such as The preferred base for this component substitution is n-butyl Lithium. This proton deprotonation reaction is carried out in tetrahydrofuran. In a dry organic solvent such as orchid or 1,2-dimethoxyethane at a temperature of about -25 ° C Done.   Without isolation of the benzyl anion, the compound of formula P-R1 (C₆H_Four) CHO (where R₁Is Condensed with a benzaldehyde compound). Preferably, about 1 equivalent Amount of benzaldehyde is added to the cold solution formed as described in the previous paragraph. You. The resulting diastereomeric mixture of condensation products can be isolated or Or could be used in the next step without isolation.   The condensation product is reacted with an acid chloride to produce an intermediate compound. The condensation product Treat with a base such as n-butyllithium, if desired, and react with the acid chloride. representative Typical acid chlorides include acyl chlorides such as acetyl chloride and benzoyl chloride, Sulfonyl chloride, benzenesulfonyl chloride, 1-butanesulfonyl chloride Lido, ethanesulfonyl chloride, isopropylsulfonyl chloride and p-tol Sulfonyl chlorides such as ruensulfonyl chloride, methoxycarbonyl chloride And alkoxycarbonyl chlorides such as benzyloxycarbonyl chloride And dialkylamido such as N, N-dimethylaminocarbonyl chloride Nocarbonyl chloride, preferably sulfonyl chloride, is included. Cold acid chloride To the reaction mixture and then warm the resulting mixture to room temperature. Preferably, condensation formation Immediately after the formation of the product, methanesulfonyl chloride is added to the reaction mixture and a further base is added. Eliminates the need to add.   The resulting intermediate compound is reacted with a second strong base to give E and Z styrylsulfoxy. A compound of formula II which is₁, R_TwoAnd R_ThreeIs the same as above) I do. Representative second strong bases for this elimination reaction include sodium methoxide, Thorium ethoxide, lithium ethoxide, lithium t-butoxide and potassium Metal alkoxides such as t-butoxide, sodium hydride, n-butyllithium Aluminum, t-butyllithium, sec-butyllithium and methyllithium. Alkyl lithium, sodium amide, magnesium diisopropylamide And metal amides such as lithium diisopropylamide. This ingredient A preferred base for substitution is potassium t-butoxide. Preferably, the second salt A 20% excess, such as 1.2 equivalents of the group, is added. Generally, this reaction is carried out at It is carried out at about room temperature, preferably at room temperature.   As shown in Reaction Scheme 4, styryl sulfoxide is benzothiophenstyryl Useful for making sulfides.                                 Reaction formula 4   These benzothiophenstyryl sulfides (where R₁And R_TwoIs the same as above Is significant) is produced from styryl sulfoxide. Generally, styryl sul Hoxide (where R₁And R_TwoIs as defined above, and R_ThreeIs heat-labile or acid-free Stability C₁-C_TenAlkyl, C_Four-C_TenAlkenyl or aryl (C₁-C_TenAlkyl) group Is added to a solution of the acid catalyst at a temperature of about 100 ° C. to about 140 ° C. (where the acid The catalyst is as defined above). The concentration of the acid catalyst depends on the final concentration of the compound of formula II Depends on the rate of addition of the compound. Styryl sulfoxide at a final concentration of about 0.2 M If added over time, the acid concentration is about 0.002M. Styryl sulfoxide Is added at a final concentration of about 0.05M over 30 minutes, the acid concentration is about 0.025M. About 1 After ２2 hours, a significant amount of the compound of formula VI is present in the reaction. Reaction time Longer, compounds of formula I are formed. Next, these compounds of formula VI are added to about 0. Treating with an additional acid, such as 5 to about 3 equivalents, and heating to about 100 ° C to about 140 ° C Could be converted to a compound of formula I. The concentration of the compound of formula VI is about 0.01 M In the range of ~ 0.5M. Suitable for the formation of compounds of formula VI and their conversion to compounds of formula I Solvents include toluene, xylene and 1,2-dichloroethane.   The compounds of formula I are useful in the synthesis of a series of 3-aroyl-2-arylbenzo [b] thiophenes. And is useful as an intermediate. U.S. Patent Nos. 4,133,814 and 4,418,068 (this Which form part of the present specification) are those 3-aroyl-2-arylbenzo [b] Thiophenes and methods for preparing them from compounds of formula I have been described. Compounds of Formula I wherein R₁And R_TwoIs hydrogen, C₁-C_FourAlkoxy or aryl These 3-aroyl-2-arylbenzo [b] thiophene groups from Scheme 5 shows an improved synthesis method of                                 Reaction formula 5   Compounds of Formula I wherein R₁And R_TwoIs hydrogen, C₁-C_FourAlkoxy or aryl Is alkoxy), boron trichloride or boron tribromide (boron trichloride is preferred). In the presence of a compound of formula XII wherein R₁₃Is chloro or hydroxy ). This reaction involves chloroform, methylene chloride, 1,2- Dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-tetrachloroethane, 1,2- Various organics such as dichlorobenzene, chlorobenzene and fluorobenzene It can be carried out in a solvent. The preferred solvent for this synthesis is 1,2-dichloro It is ethane. The reaction is carried out at a temperature from about -10C to about 25C, preferably at 0C. . The reaction is best performed at a concentration of about 0.2 M to about 1.0 M of the Formula I compound, which is benzothiophene. Well done. Generally, the acylation reaction is complete after about 2 hours to about 8 hours.   R₁And / or R_TwoIs C₁-C_FourAn alkoxy or arylalkoxy group If the acylated benzothiophene is used to isolate the product of the acylation reaction Without the compound of formula XIII (where R_FiveAnd / or R₆Is hydroxy) Is preferred. This conversion involves the addition of additional boron trichloride or boron tribromide. The reaction is performed by heating the reaction mixture. Preferably 2 to 5 boron trichloride Molar equivalents, most preferably 3 molar equivalents, are added to the reaction mixture. This reaction is performed at about 25 ° C To about 40 ° C, preferably 35 ° C. This reaction is generally performed after about 4 hours to about 48 hours. To be completed.   The acylation reaction or acylation / dealkylation reaction is carried out with an alcohol or alcohol. Stopped with a tool mix. An alcohol suitable for use in stopping the reaction The tools include methanol, ethanol and isopropanol. Preferred Alternatively, the acylation / dealkylation reaction mixture can be combined with ethanol and methanol at 95: 5 Add to mixture (3A ethanol). Bring 3A ethanol to room temperature or heat It can be refluxed (preferably heated under reflux). When stopping the reaction in this way The compound of formula XIII is conveniently crystallized from the resulting alcohol mixture. General Typically, use 1.25 mL to 3.75 mL of alcohol per 1 mmol of benzothiophene starting material You.   The following examples further illustrate the present invention. The examples do not limit the scope of the invention in any way. And should not be construed as such. All tests are performed on dry nitrogen Performed under positive pressure. All solvents and reagents used were as indicated. Percent Di is a high performance liquid chromatography (HPLC) solvent (calculated based on volume (v / v)) Calculated based on weight (w / w), except for Proton nuclear magnetic resonance (¹H NMR) Spectrum and¹³C nuclear magnetic resonance (¹³(C NMR) spectra are from Bruker AC-300 FTNMR Using a spectrophotometer, 300.135 MHz or 75.4 for proton and carbon, respectively. Obtained at 69 MHz or 300.15 MHZ using a GE QE-300 spectrophotometer. Silica gel Rash chromatography uses silica gel 60 (230-400 mesh, E. Merck) (See Still et al., J. Org. Chem., 43, 2923 (1978)). See). Elemental analysis of carbon, hydrogen and nitrogen is available from Control Equipment Corporation 44 0 Performed using Elemental Analyzer. Elemental analysis of sulfur, Brinkman Colorimet This was performed using a ric Elemental Analyzer. Melting points were determined using a Mel-Temp II melting point apparatus. Measured in open glass capillaries (without correction). Field disorpe (Field desorption) mass spectrum (FDMS) is available from Varian Instruments VG Obtained using 70-SE or VG ZAB-3F mass spectrometer. High resolution free atom impact mass Spectra (FABMS) were obtained using a Varian Instruments VG ZAB-2SE mass spectrometer. Was.   6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene yield in the reaction system (rate ) Is determined by High Performance Liquid Chromatography (HPLC) and published synthetic route (US Pat. No. 4,133,814) No.). Generally, a sample of the reaction mixture is diluted with acetonitrile, and Zorbax (registered ®) RX-C8 column (4.6 mm x 25 cm) and UV detection (280 nm) The diluted samples were assayed. The following linear-gradient solvent system was used in this analysis.Gradient solvent system   6-hydroxy-2- (4-hydroxy-phenyl) -3- [4- (2-piperidino) in crystalline material Amount (percentage) of ethoxy) benzoyl] -benzo [b] thiophene hydrochloride (power Value) was determined by the following method. Crystal solid sample (5 mg) in a 100-mL volumetric flask Weighed into 70 mM potassium phosphate buffer (pH 2.0) and 70/30 of acetonitrile. (v / v) Diluted with the mixture. An aliquot of this solution (10 μL) was used for the Zorbax® Rx High performance using -C8 column (25 cm x 4.6 mm ID, 5μ particles) and UV detection (280 nm) Assay was performed by high performance liquid chromatography. The following gradient solvent system was used.Gradient solvent system (titer)   6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoe) in the sample Toxi) benzoyl] benzo [b] thiophene hydrochloride percentage The peak area, slope (m) and intercept (b) of the line were calculated using the following equation:   Amount (percentage) of solvent, such as 1,2-dichloroethane, in which crystalline material is present ) Was measured by gas chromatography. Crystal solid sample (50 mg) in 10-mL volume Measure into a flask and dissolve 2-butanol (0.025 mg / mL) in dimethyl sulfoxide. Diluted with liquid. This solution sample was applied to a DB Wax column (30 mx 0.53 mm ID, 1μ particle ) Using gas chromatography with column flow rate of 10 mL / min and hydrogen flame ion The analysis was carried out by the fluorescence detection method. The column temperature was heated from 35 ° C to 230 ° C for 12 minutes. solvent The amount was determined by comparison with an internal standard (2-butanol).                                  Example 1   E-t-butyl 4,4'-dimethoxystilbenyl sulfoxide A. Method for producing E-t-butyl 4,4'-dimethoxystilbenyl sulfide   Chlorinate a solution of desoxy anisoin (12.82 g) in tetrahydrofuran (100 mL) Treated with titanium (IV) (10.43 g). Cool the reaction mixture during the dropwise addition of titanium (IV) chloride And maintained at a temperature of 35 ° C. or less. When the addition is complete, the resulting mixture is stirred at 30 ° C. Stirred. After an additional 30 minutes, the mixture was triturated in tetrahydrofuran (15 mL). Treat with a solution of tilamine (16.70 mL) and 2-methyl-2-propanethiol (6.76 mL). I understood. The resulting mixture was stirred at 50 ° C. After 2 hours, the mixture is quenched with 10% sodium carbonate. Added to lium (500 mL). The resulting mixture was extracted with methylene chloride. Mixed chloride The methylene extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to an oil. 17.2 g were obtained, which was cooled to room temperature and crystallized. This crystalline material is heated in ethanol This was recrystallized from toluene to obtain 12.3 g of the title compound. Mp 71-73 ° C. C₂₀H_{twenty four}O_TwoAgainst S Theory: C, 73.13; H, 7.36; S, 9.76. Found: C, 73.37; H, 7.51; S, 9.87. B. Process for producing E-t-butyl 4,4'-dimethoxystilbenyl sulfoxide   The crystalline compound prepared as described in Example 1A was dissolved in toluene (150 mL) to give The resulting solution was cooled to about -20 ° C. The cold solution was allowed to stand for 10 minutes with peracetic acid (32% w / w in dilute acetic acid, 1 .24g). The resulting mixture was extracted with saturated sodium sulfide and brine . The organic phase was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / heptane to give the title 14.11 g of compound were obtained. 104 ° C (dec). C₂₀H_{twenty four}O_ThreeAgainst S Theory: C, 69.74; H, 7.02; S, 9.31. Found: C, 69.47; H, 7.04; S, 9.54.                                  Example 2   Z-t-butyl 4,4'-dimethoxystilbenyl sulfoxide A. Preparation of t-butyl 4-methoxybenzyl sulfide   4-methoxybenzyl alcohol (10.13 g) and 1,2-dichloroethane (120 mL) And a mixture of zinc iodide (11.7 g) at once with 2-methyl-2-propanethiol (9.92 m L). The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was washed with water (100 mL) and methylene chloride (100 mL). Take out the organic phase and use magnesium sulfate , Filtered and then concentrated under reduced pressure to give 14.4 g of an oil.¹ H NMR (CDCl_Three): δ 7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 1.3 6 (s, 9H).¹³ C NMR (CDCl_Three): δ130, 114, 56, 35, 32. C₁₂H₁₈For the OS Theory: C, 68.52; H, 8.63. Found: C, 68.80; H, 8.67. B. Preparation of Z-t-butyl 4,4'dimethoxystilbenyl sulfide   Compound prepared as described in Example 2A in tetrahydrofuran (50 mL) (2. 51g) was cooled to about -20 ° C. This cold solution is taken up in hexane (1.6M, 7.47 mL). Treated with a solution of n-butyllithium for 10 minutes. Bring the resulting solution to about 0 ° C over 35 minutes Warmed up. This cold solution was treated with p-anisaldehyde (1.46 mL). After another 15 minutes, The reaction solution was treated with methanesulfonyl chloride (0.95 mL). The resulting reaction solution Warmed to room temperature. After a further 45 minutes, the reaction mixture was washed with tetrahydrofuran (1.0 M, 12 M). .0 mL) was treated with potassium t-butoxide. After another 45 minutes, 1N hydrochloric acid (12.0 mL) was added. Addition I stopped the reaction. The organic phase is separated, dried over magnesium sulfate, filtered and then To give an oil (4.4 g).¹ H NMR (CDCl_Three): δ7.95 (d, H), 7.05 (s, H), 6.9 (d, H), 6.8 (dd, 2H), 3.75 (s , 3H), 0.95 (s, 9H).¹³ C NMR (CDCl_Three): δ153, 139, 137, 114, 56, 32. C. Method for producing z-t-butyl 4,4'-dimethoxystilbenyl sulfoxide   Using the procedure essentially as described in Example 1B, the title compound was obtained from the compound from Example 2B. Was converted to something.¹ H NMR (CDCl_Three): δ7.61 (d, H), 7.56 (d, H), 7.1 (s, H) 6.9 (dd, 2H), 3.83 (s , 3H), 1.05 (s, 9H).¹³ C NMR (CDCl_Three): δ142, 132.5, 131, 118, 117, 56, 24. C₂₀H_{twenty four}O_ThreeAgainst S Theory: C, 69.74; H, 7.02. Found: C, 69.98; H, 6.94.                                  Example 3   E and z-t-butyl 4,4'-dimethoxystilbenyl sulfoxide A. Preparation of t-butyl 4-methoxybenzyl sulfide   4-methoxybenzyl alcohol (10.13 g) and 1,2-dichloroethane (120 mL) And a mixture of zinc iodide (11.7 g) at once with 2-methyl-2-propanethiol (9.92 mL) Processed. The resulting mixture was stirred at room temperature. After about 18 hours, the reaction was washed with water (100 mL ) And methylene chloride (100 mL). Take out the organic phase and add magnesium sulfate Dried with a filter, filtered and concentrated under reduced pressure to give 14.4 g of an oil.¹ H NMR (CDCl_Three): δ 7.28 (d, 2H), 6.85 (d, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 1.3 6 (s, 9H).¹³ C NMR (CDCl_Three): δ130, 114, 56, 35, 32. C₁₂H₁₈For the OS Theory: C, 68.52; H, 8.63. Found: C, 68.80; H, 8.67. B. Method for producing t-butyl 4-methoxybenzyl sulfoxide   Compound (1) prepared as described in Example 3A in 1,2-dichloroethane (50 mL) The solution of 4.4 g) was cooled to about 5 ° C and the cooled solution was added with peracetic acid (32% w / w in dilute acetic acid, 14.2 mL). ) For 30 minutes. When the peracetic acid addition is complete, the reaction is washed with brine and bicarbonate. Treated with thorium. Remove the organic phase, dry over magnesium sulfate, filter, It was then concentrated to give a yellow precipitate. The residue was treated with hexane (100 mL) to give The resulting mixture was stirred at room temperature. Filter the mixture for about 18 hours and remove the solids (100 mL). The solid was dried under reduced pressure to give 14.07 g of the title compound. 124-126 ° C.¹ H NMR (CDCl_Three): δ 7.26 (d, 2H), 6.89 (d, 2H), 3.79 (d, H), 3.78 (s, 3H), 3.58 (d, H), 1.3 (s, 9H)¹³ C NMR (CDCl_Three): δ 132, 114, 56, 53, 23. C₁₂H₁₈O_TwoAgainst S Theory: C, 63.68; H, 8.02. Found: C, 63.72; H, 7.93. C. Process for producing E and Z-t-butyl 4,4'-dimethoxystilbenyl sulfoxide   Compound prepared as described in Example 3B in tetrahydrofuran (140 mL) ( 10.0 g) of the solution was cooled to about -30 to -25 ° C (dry ice / acetone bath). This cold melting The liquid was treated with n-butyllithium in cyclohexane (1.6M, 27.65mL) for 25 minutes. Three After stirring for 5 minutes, the reaction mixture was treated with p-anisaldehyde (5.4 mL). dry The ice / acetone bath was removed and the reaction was warmed to about 20 ° C. This mixture is Treated with rufonyl chloride (3.5 mL). The temperature of the reaction is adjusted to methanesulfonyl chloride. The temperature was raised from about 20 ° C to about 35 ° C while adding the lid. Cool the mixture to about 25 ° C, then And treated with potassium t-butoxide in tetrahydrofuran (1M, 50.9 mL). Was. Stirred for an additional 35 minutes, then treated the reaction with 1N hydrochloric acid (51.0 mL). Phase Separate, dry the organic layer over magnesium sulfate, filter, and concentrate to an oil (16.67 g) I got This material was used in the next step without further purification. Carbon and carbon Roton NMR spectra were obtained for the compounds prepared as described in Examples 1 and 2. It was similar to that obtained.                                  Example 4   E and Z-3- (4,4'-dimethoxystilbenyl sulfide) -6-methoxy-2- (4-meth Toxiphenyl) benzo [b] thiophene   Heat the solution of p-toluenesulfonic acid monohydrate (552 mg) in toluene (111 mL) Flushed and water was removed by collecting in a Dean-Stark trap. Toluene (34mL ), A solution of the compound (10 g) prepared as described in Example 1 was refluxed for 6 hours. Added to the acid solution. After a further 2 hours, the mixture was cooled to 0 ° C. After another 18 hours, The cold mixture was filtered and the precipitated 6-methoxy-2- (4-methoxyphenyl) benzo [b] thio I took out the fen. The filtrate was extracted with an equal volume of saturated sodium bicarbonate solution. Organic The phases were separated, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give an orange oil 4.8 g of the product were obtained. The oil was separated into two parts, each with hexane / acetic acid Purified using silica gel flash chromatography, eluting with chill (3.5: 1) did. The fraction obtained in the desired regioisomer was concentrated to an oil. This oil is Treatment with ethyl ether selectively crystallized the first eluting regioisomer (155 mg). This The mother liquors from these crystallizations were enriched in late eluting regioisomers. Initial eluting isomer¹ H NMR (CDCl3): δ 7.71 (d, 2H), 7.64 (d, 1H), 7.46 (d, 2H), 7.06 (d, 1H), 6 .94 (d, 2H), 6.92 (d, 2H), 5.90 (m, 1H), 6.85 (d, 2H), 6.59 (s, 1H), 6.45 (d, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.66 (s, 3H). C₃₂H₂₉O_FourS_TwoHigh resolution FABMS for (MH +): Theoretical value: 541.1507. Found: 541.1491. Late eluting isomer¹ H NMR (CDCl_Three): δ7.90 (d, 1H), 7.62 (d, 2H), 7.24 (1H), 7.08 (d, 2H), 7.02 (d d, 1H), 6.96 (d, 2H), 6.74 to 6.71 (d, 2H), 6.70 (d, 2H), 6.55 (d, 2H), 6.21 (s , 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H) FDMS: m / z = 540 (m +)                                  Example 5   6-methoxy-2- (4-methoxyphenyl) benzo [b] thiophene   Compound (initial eluting isomer) (125 mg) prepared as described in Example 4 was added to toluene To a refluxing solution of p-toluenesulfonic acid monohydrate (4.2 mg) in toluene (1.5 mL). Six o'clock After a while, methanesulfonic acid (7.5 μL) was added to the reaction mixture. After another hour, the reaction The mixture was cooled to room temperature. The resulting mixture is diluted with acetonitrile and analyzed by HPLC. As a result, the yield of the title compound in the reaction system was 71.1%.                                  Example 6   6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) ben Zoyl] benzo [b] thiophene hydrochloride 1,2-dichloroethane solvate A. Method for producing ethyl 4- (2-piperidinoethoxy) benzoate   Ethyl 4-hydroxybenzoate (8.31 g), 1- (2-chloroethyl) piperidine Monohydrochloride (10.13 g), potassium carbonate (16.59 g), and methyl ethyl ketone (60 mL) Was heated to 80 ° C. After 1 hour, the mixture was cooled to about 55 ° C. and further treated with 1- (2 -Chloroethyl) piperidine monohydrochloride (0.92 g). 80 ° C of the resulting mixture Heated. Transfer the reaction to a silica gel plate with ethyl acetate / acetonitrile / triethyl. Monitored by thin layer chromatography (TLC) using ethylamine (10: 6: 1, v / v) - An additional portion of 1- (2-chloroethyl) piperidine hydrochloride was added to the starting 4-hydro Add until the xybenzoate ester is consumed. When the reaction is complete, mix The mixture was treated with water (60 mL) and cooled to room temperature. Discard the aqueous layer and allow the organic layer to And concentrated under reduced pressure at 40 mmHg. The resulting oil was purified without further purification. Used for the process. B. 4- (2-piperidinoethoxy) benzoic acid hydrochloride   Compound prepared as described in Example 6A (about 13.87 g) in methanol (30 mL) ) Was treated with 5N sodium hydroxide (15 mL) and heated to 40 ° C. 4 1/2 hours Thereafter, water (40 mL) was added. The resulting mixture was cooled to 5-10 ° C and concentrated hydrochloric acid (18 mL) was added. Slowly added. The title compound crystallized during the oxidation. Filtration and recovery of this crystalline product The residue was dried at 40-50 ° C under reduced pressure to give the title compound in a yield of 83%. 270-271 ° C. C. 4- (2-piperidinoethoxy) benzoyl chloride hydrochloride   Dimethylformamide (2 mL) and methylene chloride (500 mL) in Example 6B A solution of the compound prepared as described (30.01 g) was oxidized over 30-35 minutes. Treated with ril (10.5 mL). After stirring for about 18 hours, the reaction was complete by HPLC analysis. Was assayed. If the starting carboxylic acid is present, the reaction is Oxalyl may be added. When complete, evaporate the reaction solution and dry under reduced pressure. Was. Dissolve the residue in methylene chloride (200 mL) and evaporate the resulting solution to dryness did. This dissolution / evaporation procedure was repeated to give the title compound as a solid. D. 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) ben Zoyl] benzo [b] thiophene hydrochloride 1,2-dichloroethane solvate   Compound (2.92 g) prepared as described in Example 5, prepared as described in Preparation 6C A mixture of the prepared compound (3.45 g) and 1,2-dichloroethane ((52 mL) was added to about 0%. Cooled to ° C. Boron trichloride gas is condensed in a cold-graded cylinder (2.8 mL). And added to the cold mixture. After 8 hours at 0 ° C., the reaction mixture was further treated with boron trichloride. (2.8 mL). The resulting solution was heated to 35 ° C. After 16 hours, the reaction is complete did.   While maintaining the methanol at reflux temperature, add methanol (30 mL) for 20 minutes The reaction mixture was treated. The resulting slurry was stirred at 25 ° C. One hour later, The crystalline product is filtered, washed with cold methanol (8 mL), dried at 40 ° C. under reduced pressure and labeled 5.14 g of the compound were obtained. 225 ° C. Titer (HPLC): 86.8% 1,2-dichloroethane (gas chromatography): 6.5%.

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Claims (1)

[Claims] 1. formula: [Wherein, R ₁ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino, and R ₂ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino]. . 2. The compound according to claim 1, wherein R ₁ is hydrogen, C ₁ -C ₄ alkoxy or arylalkoxy, and R ₂ is hydrogen, C ₁ -C ₄ alkoxy or arylalkoxy. 3. 3. The compound according to claim 2, wherein R ₁ is hydrogen or C ₁ -C ₄ alkoxy, and R ₂ is hydrogen or C ₁ -C ₄ alkoxy. 4. _4. The compound according to claim 3, wherein R ₁ and R ₂ are C ₁ -C ₄ alkoxy. 5. 5. The compound according to claim 4, wherein R ₁ and R ₂ are methoxy. 6. formula: [Wherein, R ₁ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino, and R ₂ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino]. Comprising the steps of formula: Wherein R ₁ and R ₂ are as defined above, and R ₃ is a heat-labile or acid-labile C ₂ -C ₁₀ alkyl, C ₄ -C ₁₀ alkenyl or aryl (C ₁ -C ₁₀ alkyl) group Wherein the compound of formula II is reacted with an acid catalyst at a temperature of about 100 ° C. to about 140 ° C., wherein the concentration of the compound of formula II is about 0.05 M to about 0.2 M. 7. 7. The method according to claim 6, wherein R ₁ is hydrogen, C ₁ -C ₄ alkoxy or arylalkoxy, and R ₂ is hydrogen, C ₁ -C ₄ alkoxy or arylalkoxy. 8. Acid catalyst is methanesulfonic acid, benzenesulfonic acid, 1-naphthalenesulfonic acid, 1-butanesulfonic acid, ethanesulfonic acid, 4-ethylbenzenesulfonic acid, 1-hexanesulfonic acid, 1,5-naphthalenedisulfonic acid, 1-octane The method according to claim 7, which is selected from the group consisting of sulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, Nafion (registered trademark), Amberlyst (registered trademark) and Amberlite (registered trademark). Method. 9. Claims: The acid catalyst is selected from the group consisting of methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, Nafion (R), Amberlyst (R) and Amberlite (R). 8. The method according to 8. Ten. 10. The method according to claim 9, wherein the acid catalyst is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, Nafion (registered trademark), Amberlyst (registered trademark) and Amberlite (registered trademark). 11． The method of claim 10 R ₃ is heat-labile or acid-labile C ₂ -C ₁₀ alkyl or aryl (C ₁ -C ₁₀ alkyl) group. 12． The method of claim 11 R ₃ is heat-labile or acid-labile C ₂ -C ₁₀ alkyl group. 13. The method of claim 12 R ₃ is t- butyl. 14. The method of claim 13 R ₁ and R ₂ are C ₁ -C ₄ alkoxy. 15． The method of claim 14 R ₁ and R ₂ are methoxy. 16． 16. The method according to claim 15, wherein the acid catalyst is p-toluenesulfonic acid. 17． formula: [Wherein, R ₁ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino, and R ₂ is hydrogen, C ₁ -C ₄ alkoxy, arylalkoxy, halo or amino]. Comprising the steps of formula: [Wherein R ₁ and R ₂ are as defined above], which is treated with an acid catalyst.